SUBSTITUTED [1,2,4]TRIAZOLO[1,5-a]PYRIMIDINES AND THEIR USE AS POTASSIUM CHANNEL MODULATORS

ABSTRACT

This invention relates to novel substituted [1,2,4]triazolo[1,5-a]pyrimidines and their use as modulators of potassium channels. In other aspects the invention relates to the use of these compounds, in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL FIELD

This invention relates to novel substituted[1,2,4]triazolo[1,5-a]pyrimidines and their use as modulators ofsmall-conductance calcium-activated potassium channels (SK channels).Moreover the invention is directed to pharmaceutical compositions usefulfor the treatment or alleviation of diseases or disorders associatedwith the activity of potassium channels.

BACKGROUND ART

Three subtypes of small-conductance calcium-activated potassium channels(SK channels) have been cloned: SK1, SK2 and SK3 (corresponding toKCNN1-3 using the genomic nomenclature). The activity of these channelsis determined by the concentration of free intracellular calcium([Ca²⁺]_(i)) via calmodulin that is constitutively bound to thechannels. SK channels are tightly regulated by [Ca²⁺]_(i) in thephysiological range being closed at [Ca²⁺]_(i) up to around 0.1 μM butfully activated at a [Ca²⁺]_(i) of 1 μM. Being selective for potassium,open or active SK channels have a hyperpolarizing influence on themembrane potential of the cell. SK channels are widely expressed in thecentral nervous system. The distribution of SK1 and SK2 show a highdegree of overlap and display the highest levels of expression inneocortical, limbic and hippocampal areas in the mouse brain. Incontrast, the SK3 channels show high levels of expression in the basalganglia, thalamus and the brain stem monoaminergic neurons e.g. dorsalraphe, locus coeruleus and the ventral tegmental area (Sailer et al.:“Comparative immunohisto-chemical distribution of threesmall-conductance Ca²⁺-activated potassium channel subunits, SK1, SK2and SK3 in mouse brain”, Mol. Cell. Neurosci. 2004 26 458-469). The SKchannels are also present in several peripheral cells including skeletalmuscle, gland cells, liver cells and T-lymphocytes.

The hyperpolarizing action of active SK channels plays an important rolein the control of firing pattern and excitability of excitable cells. SKchannel inhibitors such as apamin and quaternized anlogues ofbicuculline have been demonstrated to increase excitability whereas theopener 1-EBIO is able to reduce electrical activity. In non-excitablecells where the amount of Ca²⁺ influx via voltage-independent pathwaysis highly sensitive to the membrane potential an activation of SKchannels will increase the driving force whereas a blocker of SKchannels will have a depolarising effect and thus diminish the drivingforce for calcium.

Based on the important role of SK channels in linking [Ca²⁺]_(i) andmembrane potential, SK channels are an interesting target for developingnovel therapeutic agents.

A review of SK channels and SK channel modulators may be found inLiegeois, J.-F. et al.: “Modulation of small conductancecalcium-activated potassium (SK) channels: a new challenge in medicinalchemistry”, Current Medicinal Chemistry 2003 10 625-647.

Known modulators of SK channels suffer from being large, oftenpositively charged, molecules or peptides (like apamin, scyllatoxin,tubocurarine, dequalinium chloride and UCL1684), or from having lowpotency (e.g. 1-EBIO and riluzole). Thus, there is a continued need forcompounds with an optimized pharmacological profile.

The compounds,N-{7-[1-(4-chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo-[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidineandN-{7-[1-(4-fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidineare chemical compounds which are listed at various chemical suppliers.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel substituted[1,2,4]triazolo[1,5-a]pyrimidines capable of modulating SK channels, orsubtypes of SK channels.

In one aspect, the present invention provides a compound of formula (I)

a stereoisomer or a mixture of its stereoisomers, or apharmaceutically-acceptable addition salt thereof, or an N-oxidethereof, wherein X, R¹, R², R³, R⁴, R′, R″ and R are as described below.

In another aspect, the invention provides pharmaceutical compositionscomprising an effective amount of a compound of the invention.

In further aspects the invention relates to the use of a compound of theinvention for the manufacture of a medicament for the treatment oralleviation of diseases or disorders associated with the activity ofpotassium channels, and to method of treatment or alleviation ofdisorders or conditions responsive to modulation of potassium channels.

Another embodiment of the invention is the provision of compounds withoptimal pharmacodynamic and/or pharmacokinetic properties such askinetic behavior, bioavailability, solubility, efficacy and/or adverseeffects.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

In one aspect, the present invention provides compounds of formula (I)

-   a stereoisomer or a mixture of its stereoisomers, or a    pharmaceutically-acceptable addition salt thereof, or an N-oxide    thereof, wherein-   R¹, R², R³ and R⁴, independently of each other, are hydrogen,    halogen, C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy;-   X is halogen;-   R′ and R″, independently of each other, are hydrogen or C₁₋₆-alkyl,    and-   R is hydrogen or C₁₋₆-alkyl;-   with the proviso that the compound is not-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;    or-   N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine.

In another embodiment of the invention, in formula (I), R¹, R², R³ andR⁴, independently of each other are hydrogen, halogen or C₁₋₆-alkyl. Inanother embodiment R¹, R², R³ and R⁴, independently of each other arehydrogen or C₁₋₆-alkyl. In another embodiment R¹, R², R³ and R⁴ arehydrogen. In another embodiment R¹, R² and R³ are hydrogen. In anotherembodiment R⁴ is hydrogen. In another embodiment R⁴ is halogen. Inanother embodiment R⁴ is C₁₋₆-alkyl.

In another embodiment of the invention, in formula (I), X is halogen. Inanother embodiment X is chlorine or bromine. In another embodiment X ischlorine.

In another embodiment of the invention, in formula (I), R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl. In anotherembodiment, R′ and R″, independently of each other, are hydrogen orC₂₋₆-alkyl. In another embodiment, R′ and R″ both are hydrogen. Inanother embodiment, R′ and R″ both are methyl.

In another embodiment of the invention, in formula (I), R is hydrogen orC₁₋₆-alkyl. In another embodiment of the invention, in formula (I), R ishydrogen. In another embodiment of the invention, in formula (I), R ishydrogen or C₁₋₆-alkyl, e.g. methyl, ethyl, propyl, isopropyl. Inanother embodiment of the invention, in formula (I), R is methyl.

In another embodiment of the invention, in formula (I) R¹, R², R³ andR⁴, independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″, independentlyof each other, are hydrogen or C₁₋₆-alkyl, and R is hydrogen orC₂₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is halogen; R′ and R″, independently ofeach other, are hydrogen or C₁₋₆-alkyl, and R is hydrogen or C₂₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is halogen; R′ and R″, independently ofeach other, are hydrogen or C₁₋₆-alkyl, and R is hydrogen.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is halogen; R′ and R″, independently ofeach other, are hydrogen or C₁₋₆-alkyl, and R is C₂₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is chlorine; R′ and R″, independently ofeach other, are hydrogen or C₁₋₆-alkyl, and R is hydrogen.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is chlorine; R′ and R″, independently ofeach other, are hydrogen or C₁₋₆-alkyl, and R is C₂₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R², R³ andR⁴, independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″, independentlyof each other, are hydrogen or C₂₋₆-alkyl, or R′ and R″ both arehydrogen; or R′ and R″ both are methyl; and R is hydrogen or C₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is halogen; R′ and R″, independently ofeach other, are hydrogen or C₂₋₆-alkyl, or R′ and R″ both are hydrogen;or R′ and R″ both are methyl; and R is C₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R² and R³ arehydrogen, R⁴ is C₁₋₆-alkyl; X is chlorine; R′ and R″, independently ofeach other, are hydrogen or C₂₋₆-alkyl, or R′ and R″ both are hydrogen;or R′ and R″ both are methyl; and R is C₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R², and R³,independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; R⁴ is hydrogen, halogen, C₂₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is chlorine, bromine or iodine; R′ andR″, independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R², and R³,independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; R⁴ is hydrogen, halogen, C₂₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is chlorine, bromine or iodine; R′ andR″, independently of each other, are hydrogen or C₁₋₆-alkyl, and R isC₁₋₆-alkyl.

In another embodiment of the invention, in formula (I)R¹, R², R³, andR⁴, independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is bromine; R′ and R″, independentlyof each other, are hydrogen or C₁₋₆-alkyl, and R is hydrogen orC₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R², and R³,independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; R⁴ is hydrogen or halogen; X ischlorine, bromine or iodine; R′ and R″, independently of each other, arehydrogen or C₁₋₆-alkyl, and R is hydrogen or C₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R², R³ and R⁴are hydrogen; X is chlorine, bromine or iodine; R′ and R″, independentlyof each other, are hydrogen or C₁₋₆-alkyl, and R is hydrogen orC₁₋₆-alkyl.

In another embodiment of the invention, in formula (I) R¹, R², and R³,independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; R⁴ is or halogen; X is chlorine, bromineor iodine; R′ and R″, independently of each other, are hydrogen orC₁₋₆-alkyl, and R is hydrogen or C₁₋₆-alkyl.

In another embodiment of the invention, the compound of the inventionis:

-   N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methylethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   or a stereoisomer or a mixture of its stereoisomers or a    pharmaceutically-acceptable addition salt thereof, or an N-oxide    thereof.

In another embodiment, the invention relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of the formula (I)

-   a stereoisomer or a mixture of its stereoisomers, or a    pharmaceutically-acceptable addition salt thereof, or an N-oxide    thereof, wherein-   R¹, R², R³ and R⁴, independently of each other, are hydrogen,    halogen, C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy;-   X is halogen;-   R′ and R″, independently of each other, are hydrogen or C₁₋₆-alkyl,    and-   R is hydrogen or C₁₋₆-alkyl.

In another embodiment of the invention, in the pharmaceuticalcomposition, in formula (I), R¹, R², R³ and R⁴, independently of eachother, are hydrogen, halogen, or C₁₋₆-alkyl; X is halogen; R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl.

In another embodiment, in the pharmaceutical composition, in formula(I), R¹, R², R³ and R⁴, independently of each other, are hydrogen orC₁₋₆-alkyl; X is halogen; one of R′ and R″, is hydrogen, and the otherone of R′ and R″ is C₁₋₆-alkyl, and R is C₁₋₆-alkyl.

In another embodiment, in the pharmaceutical composition, in formula(I), R¹, R², R³ and R⁴, independently of each other, are hydrogen orC₁₋₆-alkyl; X is halogen; one of R′ and R″, is hydrogen, and the otherone of R′ and R″ is C₁₋₆-alkyl, and R is C₁₋₆-alkyl.

In another embodiment, in the pharmaceutical composition, in formula(I), R¹, R², R³ and R⁴ are hydrogen; X is halogen; one of R′ and R″, ishydrogen, and the other one of R′ and R″ is methyl, and R is C₁₋₃-alkyl.

In another embodiment of the invention, in the pharmaceuticalcomposition, the compound is:

-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Fluorophenoxy)ethyl]-1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Bromophenoxy)ethyl]-1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Chlorophenoxy)ethyl]-1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   or a stereoisomer or a mixture of its stereoisomers, or a    pharmaceutically-acceptable addition salt thereof, or an N-oxide    thereof.

In another embodiment, the invention relates to the use of the compoundof formula (I)

-   a stereoisomer or a mixture of its stereoisomers, or a    pharmaceutically-acceptable addition salt thereof, or an N-oxide    thereof, wherein-   R¹, R², R³ and R⁴, independently of each other, are hydrogen,    halogen, C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy;-   X is halogen;-   R′ and R″, independently of each other, are hydrogen or C₁₋₆-alkyl,    and-   R is hydrogen or C₁₋₆-alkyl; for the manufacture of a pharmaceutical    composition.

In another embodiment, the invention relates to the use of the compoundof formula (I) wherein

-   R¹, R², R³ and R⁴, independently of each other, are hydrogen,    halogen, C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy;-   X is halogen;-   R′ and R″, independently of each other, are hydrogen or C₁₋₆-alkyl,    and-   R is hydrogen or C₁₋₆-alkyl; for the manufacture of a pharmaceutical    composition for the treatment, prevention or alleviation of a    disease or a disorder or a condition of a mammal, including a human,    which disease, disorder or condition is responsive to modulation of    SK channels.

In another embodiment the compound for use according to the invention isof formula (I), wherein R¹, R², R³ and R⁴, independently of each other,are hydrogen, halogen, or C₁₋₆-alkyl; X is halogen; R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl.

In another embodiment the compound for use according to the invention isof formula (I), wherein R¹, R², R³ and R⁴, independently of each other,are hydrogen or C₁₋₆-alkyl; X is halogen; one of R′ and R″, is hydrogen,and the other one of R′ and R″ is C₁₋₆-alkyl, and R is C₁₋₆-alkyl.

In another embodiment the compound for use according to the invention isof formula (I), wherein R¹, R², R³ and R⁴, independently of each other,are hydrogen or C₁₋₆-alkyl; X is halogen; one of R′ and R″, is hydrogen,and the other one of R′ and R″ is C₁₋₆-alkyl, and R is C₁₋₆-alkyl.

In another embodiment the compound for use according to the invention isof formula (I), wherein R¹, R², R³ and R⁴ are hydrogen; X is halogen;one of R′ and R″, is hydrogen, and the other one of R′ and R″ is methyl,and R is C₁₋₃-alkyl.

In another embodiment the compound for use according to the inventionis:

-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine;-   N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;-   or a stereoisomer or a mixture of its stereoisomers, or a    pharmaceutically-acceptable addition salt thereof, or an N-oxide    thereof.

Any combination of two or more of the embodiments described herein isconsidered within the scope of the present invention.

Definition of Terms

As used throughout the present specification and appended claims, thefollowing terms have the indicated meaning:

The term “C₁₋₆-alkyl” as used herein means a saturated, branched orstraight hydrocarbon group having from 1-6 carbon atoms, e.g.C₁₋₃-alkyl, C₁₋₄-alkyl, C₁₋₆-alkyl, C₂₋₆-alkyl, C₃₋₆-alkyl, and thelike. Representative examples are methyl, ethyl, propyl (e.g. prop-1-yl,prop-2-yl (or iso-propyl)), butyl (e.g. 2-methylprop-2-yl (ortert-butyl), but-1-yl, but-2-yl), pentyl (e.g. pent-1-yl, pent-2-yl,pent-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl, hexyl (e.g. hex-1-yl),and the like.

The term “halo” or “halogen” means fluorine, chlorine, bromine oriodine.

The term “hydroxy” shall mean the radical —OH.

The term “C₁₋₆-alkoxy” as used herein refers to the radical—O—C₁₋₆-alkyl. Representative examples are methoxy, ethoxy, propoxy(e.g. 1-propoxy, 2-propoxy), butoxy (e.g. 1-butoxy, 2-butoxy,2-methyl-2-propoxy), pentoxy (1-pentoxy, 2-pentoxy), hexoxy (1-hexoxy,3-hexoxy), and the like.

The term “C₃₋₇-cycloalkyl” as used herein refers to a saturatedmonocyclic carbocyclic ring having from 3 to 7 carbon atoms, e.g.C₃₋₄-alkyl, C₃₋₅-alkyl, C₃₋₆-alkyl, C₄₋₇-alkyl, C₄₋₆-alkyl, C₆₋₇-alkyland the like. Representative examples are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “optionally substituted” as used herein means that the groupsin question are either unsubstituted or substituted with one or more ofthe substituents specified. When the group(s) in question is/aresubstituted with more than one substituent the substituents may be thesame or different.

Certain of the defined terms may occur more than once in the structuralformulae, and upon such occurrence each term shall be definedindependently of the other.

The term “treatment” as used herein means the management and care of apatient for the purpose of combating a disease, disorder or condition.The term is intended to include the delaying of the progression of thedisease, disorder or condition, the alleviation or relief of symptomsand complications, and/or the cure or elimination of the disease,disorder or condition. The patient to be treated is preferably a mammal,in particular a human being.

The terms “disease”, “condition” and “disorder” as used herein are usedinterchangeably to specify a state of a patient which is not the normalphysiological state of man.

The term “medicament” as used herein means a pharmaceutical compositionsuitable for administration of the pharmaceutically active compound to apatient.

The term “pharmaceutically acceptable” as used herein means suited fornormal pharmaceutical applications, i.e. giving rise to no adverseevents in patients etc.

The term “effective amount” as used herein means a dosage which issufficient in order for the treatment of the patient to be effectivecompared with no treatment.

The term “therapeutically effective amount” of a compound as used hereinmeans an amount sufficient to cure, alleviate or partially arrest theclinical manifestations of a given disease and its complications. Anamount adequate to accomplish this is defined as “therapeuticallyeffective amount”. Effective amounts for each purpose will depend on theseverity of the disease or injury as well as the weight and generalstate of the subject. It will be understood that determining anappropriate dosage may be achieved using routine experimentation, byconstructing a matrix of values and testing different points in thematrix, which is all within the ordinary skills of a trained physicianor veterinary.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may exist in different stereoisomericforms—including enantiomers, diastereomers and cis-trans-isomers.

The invention includes all such stereoisomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or l- (tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Moreover, some of the chemical compounds of the invention being oximes,may thus exist in two forms, syn- and anti-form (Z- and E-form),depending on the arrangement of the substituents around the —C═N— doublebond. A chemical compound of the present invention may thus be the syn-or the anti-form (Z- and E-form), or it may be a mixture hereof.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a chemicalcompound of the invention include, without limitation, the sodium, thepotassium, the calcium, the magnesium, the zinc, the aluminium, thelithium, the choline, the lysinium, and the ammonium salt, and the like,of a chemical compound of the invention containing an anionic group.Such cationic salts may be formed by procedures well known and describedin the art.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention, including compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Methods of Preparation

The compounds of the invention may be prepared by conventional methodsof chemical synthesis, e.g. those described in the working examples. Thestarting materials for the processes described in the presentapplication are known or may readily be prepared by conventional methodsfrom commercially available chemicals.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

The compounds of the invention may be tested for their usefulness aspotassium channel modulating agents e.g. such as described in WO2006/100212.

The compounds of the invention may be tested for their ability tomodulate SK channels in vitro. Functional modulation can be determinedby measuring the compound-induced change in SK current by the patchclamp technique as described in Strøbk et al.: “Pharmacologicalcharacterization of small-conductance Ca²⁺-activated K channelsexpressed in HEK293 cells”, British Journal of Pharmacology (2000) 129,991-999. From this type of measurements the potency of a given compoundcan be determined as e.g. K_(i) or IC₅₀ values for blockers/inhibitorsand EC₅₀ values for openers/activators. Similar data can be obtainedfrom other patch clamp configurations and from channels expressedendogenously in various cell lines.

The compounds of the invention are capable of selectively modulatingSK1, SK2 and/or SK3 channels. Therefore, in another aspect, theinvention relates to the use of the compounds of the invention for themanufacture of medicaments, which medicament may be useful for thetreatment or alleviation of a disease or a disorder associated with theactivity of potassium channels, e.g. SK channels, e.g. SK1, SK2 and/orSK3 channels.

In one embodiment, the compounds of the invention show selectivity forSK3 over SK1 and SK2. In another embodiment, the compounds of theinvention show selectivity for SK1 over SK2 and SK3. In anotherembodiment, the compounds of the invention show selectivity for SK2 overSK1 and SK3.In another embodiment, the compounds of the invention arepositive SK channel modulators, such as positive SK3 channel modulators.In another embodiment, the compounds of the invention are negativemodulators, such as negative SK3 channel modulators. In anotherembodiment, the compounds of the invention are SK channel blockers, suchas SK3 channel blockers.

In another embodiment, the compound of the invention is considereduseful for the treatment, prevention or alleviation of a disease or adisorder or a condition responsive to modulation of SK channels.

In another embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of absence seizures,of absence seizures, agerelated memory loss, addiction, Alzheimer'sdisease, angina pectoris, arrhythmia, asthma, anxiety, ataxia, attentiondeficits, baldness, bipolar disorder, bladder hyperexcitability, bladderoutflow obstruction, bladder spasms, brain tumours, cancer,cardiovascular disorders, cerebral ischaemia, chronic obstructivepulmonary disease (COPD), cognitive dysfunction, colitis, constipation,convulsions, coronary artery spasms, coronary heart disease, cysticfibrosis, dementia, depression, diabetes type II, dyskinesia,dysmenorrhoea, eating disorder, epilepsy, erectile dysfunction,gastrointestinal dysfunction, gastroesophageal reflux disorder,gastrointestinal hypomotility disorders, gastrointestinal motilityinsufficiency, hair loss, hearing loss, hyperinsulinemia, hypertension,immune suppression, inflammatory bowel disease, inflammatory pain,intermittent claudication, interstitial cystitis (IC), irritable bowelsyndrome, ischaemia, ischaemic heart disease, learning deficiencies,mania, manic depression, memory and attention deficits, migraine, mooddisorders, motor neuron diseases, myokymia, myotonic dystrophy, myotonicmuscle dystrophia, narcolepsy, neuropathic pain, overactive bladder(OAB), pain, Parkinson's disease, polycystic kidney disease,postoperative ileus, premature labour, psychosis, psychotic disorders,renal disorders, Reynaud's disease, rhinorrhoea, secretory diarrhoea,seizures, Sjogren's syndrome, sleep disorders, sleep apnea, spasticity,stroke, traumatic brain injury, trigeminal neuralgia, urinaryincontinence, urinogenital disorders, vascular spasms, vision loss, andxerostomia.

In another embodiment the compounds of the invention are considereduseful for the treatment, prevention or alleviation of parkinsonism,dementia of ageing, senile dementia, acquired immunodeficiency syndromedementia complex, memory dysfunction in ageing, pseudodementia, memoryloss, attention deficit hyperactivity disorder, chronic fatiguesyndrome, premenstrual syndrome, late luteal phase syndrome,post-traumatic syndrome, obesity, eating disorder, bulimia, anorexianervosa, binge eating disorder (BED), premature ejaculation, erectiledifficulty, social phobia, panic disorder, autism, trichotillomania,mutism, akinetic mutism, hysterical mutism, selective mutism, hearingmutism, Gilles de la Tourettes disease, Ganser's syndrome, narcolepsy,addiction, e.g. drug addiction, drug misuse, cocaine abuse, nicotineabuse, tobacco abuse, alcohol addiction or alcoholism, or withdrawalsymptoms caused by termination of abuse of chemical substances, e.g.opioids, heroin, cocaine and morphine, and alcohol.

In another embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of a respiratorydisease, urinary incontinence, erectile dysfunction, anxiety, epilepsy,psychosis, schizophrenia, bipolar disorder, depression, amyotrophiclateral sclerosis (ALS), Parkinson's disease or pain.

In another embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of psychosis,schizophrenia, bipolar disorder, depression, epilepsy, Parkinson'sdisease or pain. In another embodiment, the compounds of the inventionare considered useful for the treatment, prevention or alleviation ofpain, mild or moderate or severe pain, pain of acute, chronic orrecurrent character, pelvic pain or abdominal pain, pain caused bymigraine, postoperative pain, phantom limb pain, inflammatory pain,neuropathic pain, chronic headache, central pain, pain related todiabetic neuropathy, to post therapeutic neuralgia, or to peripheralnerve injury.

In another embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of depression. Inanother embodiment, the compounds of the invention are considered usefulfor the treatment, prevention or alleviation of cardiovasculardisorders. In another embodiment, the compounds of the invention areconsidered useful for the treatment, prevention or alleviation ofcognitive dysfunction. In another embodiment, the compounds of theinvention are considered useful for the treatment, prevention oralleviation of diabetes type II. In another embodiment, the compounds ofthe invention are considered useful for the treatment, prevention oralleviation of gastrointestinal dysfunction. In another embodiment, thecompounds of the invention are considered useful for the treatment,prevention or alleviation of hypertension. In another embodiment, thecompounds of the invention are considered useful for the treatment,prevention or alleviation of hypertension of overactive bladder (OAB).In another embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of pain. In anotherembodiment, the compounds of the invention are considered useful for thetreatment, prevention or alleviation of Parkinson's disease. In anotherembodiment, the compounds of the invention are considered useful for thetreatment, prevention or alleviation of urinary incontinence. In anotherembodiment, the compounds of the invention are considered useful for thetreatment, prevention or alleviation of ataxia. In another embodiment,the compounds of the invention are considered useful for the treatment,prevention or alleviation of amyotrophic lateral sclerosis (ALS).

The compounds tested showed a biological activity determined asdescribed herein in the micromolar and sub-micromolar range, i.e. offrom below 1 to above 100 μM e.g. from below 0.1 to about 10 μM.

Pharmaceutical Compositions

In yet another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thecompounds of the invention.

While a compound of the invention for use in therapy may be administeredin the form of the raw chemical compound, it is preferred to introducethe active ingredient, optionally in the form of a physiologicallyacceptable salt, in a pharmaceutical composition together with one ormore adjuvants, excipients, carriers and/or diluents.

In another embodiment, the invention provides pharmaceuticalcompositions comprising the compound of the invention, or apharmaceutically acceptable salt or compound thereof, together with oneor more pharmaceutically acceptable carriers therefore and, optionally,other therapeutic and/or prophylactic ingredients. The carrier(s) mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof. Such forms include solids, and inparticular tablets, filled capsules, powder and pellet forms, andliquids, in particular aqueous or non-aqueous solutions, suspensions,emulsions, elixirs, and capsules filled with the same, all for oral use,suppositories for rectal administration, and sterile injectablesolutions for parenteral use. Such pharmaceutical compositions and unitdosage forms thereof may comprise conventional ingredients inconventional proportions, with or without additional active compounds orprinciples, and such unit dosage forms may contain any suitableeffective amount of the active ingredient commensurate with the intendeddaily dosage range to be employed.

The compound of the present invention can be administered in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a chemical compound of the invention or apharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compound according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the chemical compoundaccording to the invention may be formulated as ointments, creams orlotions, or as a transdermal patch. Ointments and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilising agents, dispersing agents,suspending agents, thickening agents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

In one embodiment, the invention provides tablets or capsules for oraladministration

In another embodiment, the invention provides and liquids forintravenous administration and continuous infusion.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated and the route of administration, and is within thediscretion of the physician, and may be varied by titration of thedosage to the particular circumstances of this invention to produce thedesired therapeutic effect. However, it is presently contemplated thatpharmaceutical compositions containing of from about 0.1 to about 500 mgof active ingredient per individual dose, e.g. from about 1 to about 100mg, e.g. from about 1 to about 10 mg, are suitable for therapeutictreatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Other ranges are from about 0.1 μg/kg to about 10 mg/kg/dayi.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the prevention,treatment or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to modulation of potassium channels, inparticular SK channels, and which method comprises comprisingadministering to such a living animal body, including a human, in needthereof a therapeutically-effective amount of a compound of theinvention.

The indications contemplated according to the invention are those statedabove.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, or 30-100 milligramsdaily, dependent as usual upon the exact mode of administration, form inwhich administered, the indication toward which the administration isdirected, the subject involved and the body weight of the subjectinvolved, and further the preference and experience of the physician orveterinarian in charge.

A satisfactory result can, in certain instances, be obtained at a dosageas low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper limit of thedosage range is about 10 mg/kg i.v. and 100 mg/kg p.o. Other ranges arefrom about 0.001 to about 1 mg/kg i.v. and from about 0.1 to about 10mg/kg p.o.

EXAMPLES

The following examples refer to intermediate compounds and finalproducts for general formula (I) identified in the specification. Thepreparation of the compounds of general formula (I) of the presentinvention is described in detail using the following examples.Occasionally, the reaction may not be applicable as described to eachcompound included within the disclosed scope of the invention. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In these cases the reactions can be successfullyperformed by conventional modifications known to those skilled in theart, which is, by appropriate protection of interfering groups, bychanging to other conventional reagents, or by routine modification ofreaction conditions. Alternatively, other reactions disclosed herein orotherwise conventional will be applicable to the preparation of thecorresponding compounds of the invention. In all preparative methods,all starting materials are known or may easily be prepared from knownstarting materials.

The abbreviations as used in the examples have the following meaning:

-   Ac: acetyl-   Et: ethyl-   Me: methyl-   EtOAc: Ethyl acetate-   rt: room temperature

Procedure A

-   Step A: A substituted phenol derivative and 3-chloro-2-butanone, or    alternatively another alpha-halogenated keto derivative, were    dissolved in acetonitrile and potassium carbonate was added. The    reaction mixture was refluxed until complete conversion of the    phenol. The mixture was then cooled to rt, filtered, evaporated    under reduced pressure and the remaining oil was then dissolved in    dichloromethane and washed with aqueous sodium carbonate and water.    The organic layer was dried, the solvent removed under reduced    pressure and the desired intermediate could be purified by    distillation or by column chromatography.-   Step B: The isolated intermediate from Step A and dimethyl formamide    dimethyl acetal (1.2 eq) were heated at 120° C. with removal of the    formed methanol. After complete reaction, the mixture was cooled to    rt and the remaining crude product was purified by column    chromatography (EtOAc/hexane) or used without further purification    in the subsequent reaction step.-   Step C: The intermediate from Step B and diamino-1,2,4-triazole (1    eq) were dissolved in acetic acid and heated to reflux for 30-60    min. The reaction mixture was allowed to cool to rt, triturated with    diethyl ether and the desired product isolated by filtration. This    crude product could be purified by column chromatography    (dichloromethane/methanol) or used in the next step without further    purification.-   Step D: The [1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine derivative    formed in Step C was dissolved in acetonitrile and added dimethyl    formamide dimethyl acetal (1.2 eq) and the reaction mixture was    refluxed 1 h and allowed to cool to rt. The desired product could be    isolated as a solid by filtration or by removal of the solvent under    reduced pressure. The crude product was used without further    purification in Step E.-   Step E: The    N,N-dimethyl-N′-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl-formamidine    derivative from Step D and the required hydroxylamine derivative (1    eq) were dissolved in methanol, heated to reflux and cooled to rt.    The desired product was isolated as a solid after filtration and    washing with methanol or by purification using column    chromatography.

An example of Procedure A, the preparation ofN-{7-[1-(4-bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine,is shown in Scheme 1.

Example A

N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine

The title compound, listed at various chemical suppliers, is prepared asdescribed in Procedure A.

Example BN-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine

The title compound, listed at various chemical suppliers, is prepared asdescribed in Procedure A.

Example 1N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 4-bromophenol and 3-chloro-2-butanone) and isolated by filtrationto give the title compound as the parent compound.

HR-MS: 391.0531 ([M+1]⁺, C₁₅H₁₆N₆O₂Br; calc. 391.051812).

Example 2N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 2,4-dichlorophenol and 3-chloro-2-butanone) and isolated byfiltration to give the title compound as the parent compound.

HR-MS: 381.0624 ([M+1]⁺, C₁₅H₁₅N₆O₂Cl₂; calc. 381.063355).

Example 3N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 4-chlorophenol and 3-chloro-2-butanone) and isolated by filtrationto give the title compound as the parent compound.

HR-MS: 347.1039 ([M+1]⁺, C₁₅H₁₆N₆O₂Cl; calc. 347.102327).

Example 4N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 4-chloro-2-methylphenol and 3-chloro-2-butanone) and isolated byfiltration to give the title compound as the parent compound.

HR-MS: 347.1018 ([M+1]⁺, C₁₅H₁₆N₆O₂Cl; calc. 347.102327).

Example 5N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 4-chloro-2-methylphenol and 3-chloro-2-butanone) and isolated byfiltration to give the title compound as the parent compound.

HR-MS: 389.1501 ([M+1]⁺, C₁₈H₂₂N₆O₂Cl; calc. 389.149277).

Example 6N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a[pyrimidin-2-yl}-N′-isopropyloxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 4-chloro-2-methyl-phenol and 3-chloro-2-butanone) and purified bycolumn chromatography to give the title compound as the parent compound.

HR-MS: 389.1490 ([M+1]⁺, C₁₈H₂₂N₆O₂Cl; calc. 389.149277).

Example 7N-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine

The title compound was prepared as described in Procedure A (startingfrom 4-chloro-2-methyl-phenol and 3-chloro-3-methyl-butanone) andisolated by filtration to give the title compound as the parentcompound.

HR-MS: 375.1325 ([M+1]⁺, C₁₇H₂₀N₆O₂Cl; calc. 375.133627).

Example 8 Biological Activity

This example demonstrates the biological activity of the compounds ofthe invention. The ionic current through small-conductanceCa²⁺-activated K⁺ channels (SK channels, subtype 1) is recorded usingthe whole-cell configuration of the patch-clamp technique in a classicpatch-clamp set-up using HEK293 tissue culture cells expressing hSK1channels as described in e.g. WO 2006/100212.

The SC₁₀₀ value determined is defined as the Stimulating Concentrationrequired for increasing the baseline current by 100%. The below SC₁₀₀values are an indication of the SK1 activating properties of thecompounds of the invention.

Example The SC₁₀₀ (μM) A 0.008 B 0.075 1 0.015 2 0.005 3 0.04 4 0.20 50.003 6 0.40 7 0.60

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notto be limited as by the appended claims.

The features disclosed in the foregoing description, in the claimsand/or in the accompanying drawings, may both separately and in anycombination thereof, be material for realising the invention in diverseforms thereof.

1.-14. (canceled)
 15. A compound of the formula (I)

a stereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable addition salt thereof, or an N-oxide thereof, wherein R¹, R²,R³ and R⁴, independently of each other, are hydrogen, halogen,C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl; with the proviso that the compound is notN-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine; orN-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine.16. A compound of the formula (I),

a stereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable addition salt thereof, or an N-oxide thereof, wherein R¹, R²,R³ and R⁴, independently of each other, are hydrogen, halogen,C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₂₋₆-alkyl.
 17. A compound of the formula (I)

a stereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable addition salt thereof, or an N-oxide thereof, wherein R¹, R²,R³ and R⁴, independently of each other, are hydrogen, halogen,C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″,independently of each other, are hydrogen or C₂₋₆-alkyl, or R′ and R″both are hydrogen; or R′ and R″ both are methyl; and R is hydrogen orC₁₋₆-alkyl.
 18. A compound of the formula (I)

a stereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable addition salt thereof, or an N-oxide thereof, wherein R¹, R²,and R³, independently of each other, are hydrogen, halogen, C₁₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; R⁴ is hydrogen, halogen, C₂₋₆-alkyl,C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is chlorine, bromine or iodine; R′ andR″, independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl.
 19. The compound according to claim 15, whichis:N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]-triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N-hydroxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine;orN-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;or a stereoisomer or a mixture of its stereoisomers, or apharmaceutically acceptable addition salt thereof, or an N-oxidethereof.
 20. A pharmaceutical composition comprising a therapeuticallyeffective amount of the compound of the formula (1)

a stereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable addition salt thereof, or an N-oxide thereof, wherein R¹, R²,R³ and R⁴, independently of each other, are hydrogen, halogen,C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl.
 21. The pharmaceutical composition according toclaim 20, wherein the compound is:N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine;orN-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;or a stereoisomer or a mixture of its stereoisomers, or apharmaceutically acceptable addition salt thereof, or an N-oxidethereof.
 22. A method of treatment, prevention or alleviation of adisease or a disorder or a condition of a living animal body, includinga human, which disorder, disease or condition is responsive tomodulation of SK channels, which method comprises the step ofadministering to such a living animal body in need thereof, atherapeutically effective amount of the compound of the formula (I)

a stereoisomer or a mixture of its stereoisomers, or a pharmaceuticallyacceptable addition salt thereof, or an N-oxide thereof, wherein R¹, R²,R³ and R⁴, independently of each other, are hydrogen, halogen,C₁₋₆-alkyl, C₃₋₇-cycloalkyl or C₁₋₆-alkoxy; X is halogen; R′ and R″,independently of each other, are hydrogen or C₁₋₆-alkyl, and R ishydrogen or C₁₋₆-alkyl.
 23. The method according to claim 22, whereinthe compound is:N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(2,4-Dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)-ethyl]-6-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-hydroxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-propyloxy-formamidine;N-{7-[1-(4-Chloro-2-methylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-isopropyloxy-formamidine;orN-{7-[1-(4-Chloro-2-methylphenoxy)-1-methyl-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}-N′-methoxy-formamidine;or a stereoisomer or a mixture of its stereoisomers, or apharmaceutically acceptable addition salt thereof, or an N-oxidethereof.
 24. The method according to claim 22, wherein the disease,disorder or condition responsive to modulation of SK channels is:absence seizures, agerelated memory loss, Alzheimer's disease, anginapectoris, arrhythmia, asthma, anxiety, ataxia, attention deficits,baldness, bipolar disorder, bladder hyperexcitability, bladder outflowobstruction, bladder spasms, brain tumors, cerebral ischaemia, chronicobstructive pulmonary disease, cancer, cardiovascular disorders,cognitive dysfunction, colitis, constipation, convulsions, coronaryartery spasms, coronary hearth disease, cystic fibrosis, dementia,depression, diabetes type II, dysmenorrhoea, epilepsy, gastrointestinaldysfunction, gastroesophageal reflux disorder, gastrointestinalhypomotility disorders gastrointestinal motility insufficiency, hearingloss, hyperinsulinemia, hypertension, immune suppression, inflammatorybowel disease, inflammatory pain, intermittent claudication, irritablebowel syndrome, ischaemia, ischaemic hearth disease, learningdeficiencies, male erectile dysfunction, manic depression, memorydeficits, migraine, mood disorders, motor neuron diseases, myokymia,myotonic dystrophy, myotonic muscle dystrophia, narcolepsy, neuropathicpain, pain, Parkinson's disease, amyotrophic lateral sclerosis (ALS),polycystic kidney disease, postoperative ileus, premature labour,psychosis, psychotic disorders, renal disorders, Reynaud's disease,rhinorrhoea, secretory diarrhoea, seizures, Sjogren's syndrome, sleepapnea, spasticity, sleeping disorders, stroke, traumatic brain injury,trigeminal neuralgia, urinary incontinence, urinogenital disorders,vascular spasms, vision loss, or xerostomia.